Estimated 1-2 percent of the population harbor abdominal aortic aneurysms (AAA). AAAs are the 13th leading cause of death in the USA with approximately 15,000 deaths/year. Familial aggregation of AAA is widely recognized and two segregation studies suggest a major gene effect. In this application, our goal is to localize the chromosomal regions likely to harbor the AAA susceptibility gene(s). To date, DNA samples have been collected from 65 affected sibling pairs for this study. Specifically, we propose to: 1) Continue to identify affected-relative-pairs with AAA and collect blood for DNA isolation from them as well as those relatives that are informative for identifying alleles shared as identical by descent. First-degree family members who are 55 years or older will be offered an abdominal ultrasonography examination to detect asymptomatic AAAs. 2) Perform model-free affected pedigree member and sib-pair analyses using two-stage design. The first stage of phase I will consist a genome scan using highly polymorphic markers located on average 10 cM apart (about 390 markers to scan all the human chromosomes) on the 65 affected sib pairs we have collected to date. The second stage of phase I will include genotyping additional markers from regions that warrant further investigation based on the first stage of phase I results. In the second phase, using the additional pairs collected in Specific Aim 1 (we expect to enroll at least 150 additional affected sib pairs selected from the families of about 2,700 AAA patients), we will type markers in chromosomal regions determined in the first stage to be sufficiently interesting, i.e. exceed standard statistical threshold, to warrant further investigation, then perform model- free linkage analyses in those regions using the combined data set. 3) To supplement the genome scan, carry out genetic association studies for selected candidate loci using DNA samples collected from unrelated AAA-patients and controls. The candidate loci to be investigated in association studies are: a) MMPs (MMP1-3, 9, 10 and 13); and b) HLA class II antigens DR, DQAl and DQB1. The long term goal of the project, although not of this grant application, is to identify the gene or genes that harbor mutations in patients with AAA. The results obtained in these studies are likely to yield important information regarding the genetic factors contributing to the development of AAA, and could provide the basis for genetic testing to identify those individuals at risk for developing AAA. Such individuals could then be monitored by ultrasonography to detect the dilatation of abdominal aorta and surgically repair the aneurysms before they rupture and lead to massive bleeding and often sudden death.